Chemistry of α-Substituted N-Nitrosamines - ACS Symposium Series

4 Chemistry of α-Substituted N-Nitrosamines M. WIESSLER

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Institute of Toxicology and Chemotherapy, German Cancer Research Center, Im Neuenheimer F e l d 280, 6900 Heidelberg, F . R . G .

A l t h o u g h the mechanism of the activation of dialkylnitrosamines seems to be e l u c i d a t e d (1,2,3) ,nothing is known about the s p e c i e s whether it be α - h y d r o x y d i alkylnitrosamines, d i a z o t a t e s (4,5) , m o n o a l k y l n i t r o s amines (6,7) or another as y e t u n d e f i n e d m o l e c u l e which is r e s p o n s i b l e f o r the alkylation of nucleic a c i d s and p r o t e i n s (8) if i n d e e d alkylation is responsible for tumor i n d u c t i o n . The purpose of our i n v e s t i g a t i o n s i s to l e a r n about the c h e m i c a l b e h a v i o r of the i n t e r m e d i ­ a t e s d i s c u s s e d above, namely to attempt t o establish any relation between the c h e m i c a l reactivity o f such s p e c i e s and their biological acitivities. The p r e s e n t work will first d i s c u s s our e f f o r t s to synthesize α -functionalized dialkyl N-nitrosamines. The second p a r t will r e p o r t on the h y d r o l y s i s of α ­ - a c e t o x y N - n i t r o s a m i n e s and the consequenses t h e r e o f . Finally the attempted s y n t h e s i s of α - p h o s p h a t e s of N­ - n i t r o s a m i n e s and their relationship to the t h e r m a l b e ­ h a v i o r of α -functionalized N - n i t r o s a m i n e s will be dis­ cussed. α

-Functionalized

N-Nitrosamines

S i n c e 1971, we have been engaged in the s y n t h e s i s of α -substituted dialkyl N - n i t r o s a m i n e s , namely α ­ -hydroxy N - n i t r o s a m i n e s . Because of the presumed h i g h reactivity of these a l c o h o l s , it seemed d e s i r a b l e to have them in a stabilized form, e.g. as e s t e r s . In 1970 Franck and h i s group r e p o r t e d a method to c o n v e r t terti­ ary amines i n t o d i a l k y l n i t r o s a m i n e s i n the p r e s e n c e o f 2 - n i t r o p r o p a n e , cuprous i o n and oxygen (9). I f the amine is s u b s t i t u t e d w i t h different a l k y l g r o u p s , these groups are cleaved statistically (Eq. 1). 0-8412-0503-5/79/47-101-057$05.00/0 ©

1979

A m e r i c a n C h e m i c a l Society

Anselme; N-Nitrosamines ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

58

N-NITROSAMINES

Ri

(1)

R -N NO

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R

Y

2

NO

NO

A p p l i c a t i o n o f the Franck r e a c t i o n t o acetoxymethyl d i ­ me t h y lamine I s y n t h e s i z e d by Bohrne (10),gave a com­ pound i d e n t i f i e d as t h e n i t r o n a t e e s t e r I I I o f hydroxym e t h y l m e t h y l n i t r o s a m i n e i n 20% y i e l d .

C H CH

3

X

N

^

3

/ C H

N

2

0 N = C I C H

3

)

2

0

/NCH20C0CH3 CH

3

ι C

H

3

^

N

/ C H

no

2

O C O C H

3

II

In s p i t e o f v a r i a t i o n s i n temperature and c o n c e n t r a t i o n , t h e r e was no e v i d e n c e f o r the p r e s e n c e o f t h e α-acet­ a t e I I . A t t h a t time, we have no e x p l a n a t i o n f o r t h e f o r m a t i o n o f t h i s n i t r o n a t e e s t e r a l t h o u g h we may now have a p o s s i b l e r a t i o n a l i z a t i o n which w i l l be d i s c u s s e d later. In 1972, E i t e r and h i s group r e p o r t e d t h e s y n t h e ­ s i s o f α-alkoxy d i a l k y l N - n i t r o s a m i n e s (11),which can be o b t a i n e d e a s i l y i n 20-50 g q u a n t i t i e s . T h i s s y n t h e ­ t i c scheme works w e l l when formaldehyde was used. I n t h o s e c a s e s when h i g h e r a l i p h a t i c a l d e h y d e s a r e used (e.g. a c e t a l d e h y d e ) , t h e y i e l d s d e c r e a s e d t o 3-5%. The α - a l k o x y d i a l k y l n i t r o s a m i n e s always c o n t a i n e d t h e t r i m e r i c p a r a l d e h y d e as i m p u r i t y . When a c e t a l d e h y d e and

Anselme; N-Nitrosamines ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

4.

wiESSLER

59

N-Nitrosamines

α-Substituted

e t h y l a m i n e a r e r e a c t e d a t - 3 0 ° and the r e s u l t i n g imine i s used w i t h o u t f u r t h e r p u r i f i c a t i o n , i t i s p o s s i b l e t o i s o l a t e t h e α - e t h e r s w i t h o u t i m p u r i t i e s i n 5% y i e l d . A l t h o u g h the c o n d i t i o n s used t o c l e a v e the e t h e r l i n k a g e a r e v i g o r o u s , we d e c i d e d t o attempt t h i s r e a c ­ t i o n on the α - a l k o x y N - n i t r o s a m i n e s . The c l e a v a g e o f e t h e r s w i t h a c e t i c a n h y d r i d e i n the p r e s e n c e o f Lewis a c i d s i s well-known i n the l i t e r a t u r e (J_2,J_3,J_4) . Reac­ t i o n o f α -methoxy d i m e t h y l n i t r o s a m i n e IV w i t h Ac20 i n the p r e s e n c e o f B F e t h e r a t e a t 60° r e s u l t e d i n the c l e a v a g e not o n l y of the C-0 bond b u t a l s o the N-C bond Π5,V6) .

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3

CH ^

CH2OCOCH3

3

Ν

CH3OCOCH3 +

NO CH ^ 3

N

/

CH 0CH 2

11

3

C H

3v.

/COCH3

(2)

ν

CH3OCH2OCOCH3

ho VI

VII

The α - a c e t a t e o f DMN I I c o u l d be i s o l a t e d i n 10-15% y i e l d a f t e r p u r i f i c a t i o n . V a r i a t i o n s o f the Lewis a c i d used f a i l e d t o improve the y i e l d s o f I I . A l l t h e o t h e r c l e a v a g e p r o d u c t s (Eq. 2) c o u l d be i s o l a t e d e x c e p t the N - m e t h y l - N - n i t r o s o a c e t a m i d e V I . I t i s well-known from the work o f Huisgen and o t h e r s (4,5, V7,J_8,J_9) t h a t Nn i t r o s a m i d e s a r e u n s t a b l e and r e a r r a n g e t o e s t e r s , i n our case t o V. T h i s was i n d i c a t e d by t h e h i g h y i e l d (50-60%) o f t h e m e t h y l e s t e r V i n c o n t r a s t t o I I , the c o u p l e d c l e a v a g e p r o d u c t . T h i s c o n c l u s i o n was c o n f i r m e d by t h e r e a c t i o n o f V I I I under analogous c o n d i t i o n s which produced V and the c o r r e s p o n d i n g e t h y l e s t e r IX as the f i n a l p r o d u c t o f t h e rearrangement o f X (Eq. 3 ) . These r e s u l t s were o b t a i n e d by gas c h r o m a t o g r a p h i c a n a l y s i s of the r e a c t i o n products. The use o f a c e t y l c h l o r i d e i n s t e a d o f a c e t i c an­ h y d r i d e w i t h o u t Lewis a c i d f o r the c l e a v a g e o f the e t h e r bond a t 10 t o 15° a l l o w e d the i s o l a t i o n o f the c h l o r o m e t h y l m e t h y l n i t r o s a m i n e XI i n 15-20% y i e l d s a f t e r two d i s t i l l a t i o n s (15,16).

Anselme; N-Nitrosamines ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

N-NITROSAMINES

60

C2Hs

xCH 0C0CH 2

x

3

+

ν

τ NO

c

2

H

5 x

N

/

C

H

2

NO

0

C

H

3

\

C H 0C0CH 2

^

3

(3)

ix

C

2H5. /C0CH N

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5

3

+

V

I

I

NO χ A g a i n a l l c l e a v a g e p r o d u c t s c o u l d be i s o l a t e d , e x c e p t VI; t h e r e was no i n d i c a t i o n t h a t I I was formed i n t h i s r e a c t i o n (Eq. 4). CH ^ /CH Cl 3

N

2

+

NO CH